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1.
Nature ; 611(7936): 603-613, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36352230

RESUMO

Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.


Assuntos
Neoplasias Colorretais , Metástase Neoplásica , Proteínas de Neoplasias , Recidiva Local de Neoplasia , Neoplasia Residual , Receptores de Superfície Celular , Animais , Humanos , Camundongos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/patologia , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Metástase Neoplásica/terapia , Modelos Animais de Doenças , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante , Imunoterapia
2.
J Exp Clin Cancer Res ; 41(1): 315, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289544

RESUMO

BACKGROUND: Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood. METHODS: LAMC2 transcriptional levels were evaluated using publicly available transcriptome data sets, and LAMC2 immunohistochemistry was performed using a tissue microarray composed of PDAC and normal pancreas tissues. Silencing and tracing of LAMC2 was performed using lentiviral shRNA constructs and CRISPR/Cas9-mediated homologous recombination, respectively. The contribution of LAMC2 to PDAC tumorigenicity was explored in vitro by tumor cell invasion, migration, sphere-forming and organoids assays, and in vivo by tumor growth and metastatic assays. mRNA sequencing was performed to identify key cellular pathways upregulated in LAMC2 expressing cells. Metastatic spreading induced by LAMC2- expressing cells was blocked by pharmacological inhibition of transforming growth factor beta (TGF-ß) signaling. RESULTS: We report a LAMC2-expressing cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation and differentiation, and drives metastasis. mRNA profiling of these cells indicates a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-ß signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of the TGF-ß type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated lung metastasis, primarily originating from LAMC2-expressing cells. CONCLUSIONS: We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I , RNA Interferente Pequeno , Neoplasias Pancreáticas/patologia , Células-Tronco Neoplásicas/metabolismo , Fator de Crescimento Transformador beta , RNA Mensageiro , Receptores de Ativinas , Movimento Celular/genética , Linhagem Celular Tumoral , Laminina/genética , Laminina/metabolismo , Neoplasias Pancreáticas
3.
Nat Cancer ; 3(9): 1052-1070, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35773527

RESUMO

Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5+ tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5+ cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a+ cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a+ cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a+ cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP+ fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC.


Assuntos
Neoplasias Colorretais , Organoides , Animais , Diferenciação Celular , Neoplasias Colorretais/tratamento farmacológico , Camundongos , Células-Tronco Neoplásicas , Recidiva
4.
Theranostics ; 11(12): 5686-5699, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897875

RESUMO

Background: Colorectal cancer (CRC) is currently the third leading cause for cancer-related mortality. Cancer stem cells have been implicated in colorectal tumor growth, but their specific role in tumor biology, including metastasis, is still uncertain. Methods: Increased expression of L1CAM, CXCR4 and NODAL was identified in tumor section of patients with CRC and in patients-derived-organoids (PDOs). The expression of L1CAM, CXCR4 and NODAL was evaluated using quantitative real-time PCR, western blotting, immunofluorescence, immunohistochemistry and flow cytometry. The effects of the L1CAM, CXCR4 and NODAL on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. Results: We found that human colorectal cancer tissue contains cancer stem cells defined by L1CAMhigh/CXCR4high expression that is activated by Nodal in hypoxic microenvironment. This L1CAMhigh/CXCR4high population is tumorigenic, highly resistant to standard chemotherapy, and determines the metastatic phenotype of the individual tumor. Depletion of the L1CAMhigh/CXCR4high population drastically reduces the tumorigenic potential and the metastatic phenotype of colorectal tumors. Conclusion: In conclusion, we demonstrated that a subpopulation of migrating L1CAMhigh/CXCR4high is essential for tumor progression. Together, these findings suggest that strategies aimed at modulating the Nodal signaling could have important clinical applications to inhibit colorectal cancer-derived metastasis.


Assuntos
Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Metástase Neoplásica/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Proteína Nodal/metabolismo , Organoides/metabolismo , Receptores CXCR4/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Neoplasias Colorretais/patologia , Humanos , Camundongos , Organoides/patologia , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologia
5.
Cell Stem Cell ; 26(6): 845-861.e12, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32396863

RESUMO

Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here, we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RNA polymerase I subunit A (POLR1A). Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest on CRCs. We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5- tumor cells. Therefore, a common architecture in CRCs is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins.


Assuntos
Neoplasias Colorretais , Células-Tronco Neoplásicas , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , DNA Ribossômico , Humanos , Receptores Acoplados a Proteínas G
6.
Oncogene ; 39(21): 4271-4285, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32291413

RESUMO

Pancreatic stellate cells (PSCs) secrete high levels of transforming growth factor-ß1 (TGF-ß1) that contributes to the development of pancreatic ductal adenocarcinoma (PDAC). TGF-ß1 modulates the expression of L1 cell adhesion molecule (L1CAM), but its role in tumour progression still remains controversial. To clarify L1 function in PDAC and cellular phenotypes, we performed L1CAM cell sorting, silencing and overexpression in several primary pancreatic cancer cells. PSCs silenced for TGF-ß1 were used for crosstalk experiments. We found that TGF-ß1 secreted by PSCs negatively regulates L1CAM expression, through canonical TGF-ß-Smad2/3 signalling, leading to a more aggressive PDAC phenotype. Cells with reduced expression of L1CAM harboured enhanced stemness potential and tumourigenicity. Inactivation of TGF-ß1 signalling in PSCs strongly reduced the aggressiveness of PDAC cells. Our data provide functional proof and mechanistic insights for the tumour-suppressive function of L1CAM via reducing stemness. Rescuing L1CAM expression in cancer cells through targeting of TGF-ß1 reverses stemness and bears the potential to improve the still miserable prognosis of PDAC patients.


Assuntos
Carcinogênese/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Molécula L1 de Adesão de Célula Nervosa/biossíntese , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Humanos , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Molécula L1 de Adesão de Célula Nervosa/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Células Estreladas do Pâncreas/patologia , Fator de Crescimento Transformador beta1/genética
7.
Nature ; 554(7693): 538-543, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29443964

RESUMO

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFß levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFß-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFß unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFß signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGFß in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFß signalling may therefore have broad applications in treating patients with advanced colorectal cancer.


Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Evasão da Resposta Imune , Imunoterapia , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Fator de Crescimento Transformador beta/imunologia , Alelos , Animais , Diferenciação Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Mutação , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/patologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
8.
EMBO Mol Med ; 9(7): 869-879, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28468934

RESUMO

The analysis of stem cell hierarchies in human cancers has been hampered by the impossibility of identifying or tracking tumor cell populations in an intact environment. To overcome this limitation, we devised a strategy based on editing the genomes of patient-derived tumor organoids using CRISPR/Cas9 technology to integrate reporter cassettes at desired marker genes. As proof of concept, we engineered human colorectal cancer (CRC) organoids that carry EGFP and lineage-tracing cassettes knocked in the LGR5 locus. Analysis of LGR5-EGFP+ cells isolated from organoid-derived xenografts demonstrated that these cells express a gene program similar to that of normal intestinal stem cells and that they propagate the disease to recipient mice very efficiently. Lineage-tracing experiments showed that LGR5+ CRC cells self-renew and generate progeny over long time periods that undergo differentiation toward mucosecreting- and absorptive-like phenotypes. These genetic experiments confirm that human CRCs adopt a hierarchical organization reminiscent of that of the normal colonic epithelium. The strategy described herein may have broad applications to study cell heterogeneity in human tumors.


Assuntos
Técnicas de Cultura de Células/métodos , Neoplasias Colorretais/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Organoides , Animais , Diferenciação Celular , Proliferação de Células , Feminino , Edição de Genes/métodos , Técnicas de Introdução de Genes , Genes Reporter , Proteínas de Fluorescência Verde/análise , Proteínas de Fluorescência Verde/genética , Xenoenxertos , Humanos , Camundongos SCID , Receptores Acoplados a Proteínas G/genética , Coloração e Rotulagem/métodos
9.
Cell Stem Cell ; 20(6): 801-816.e7, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28285904

RESUMO

Highly proliferative Lgr5+ stem cells maintain the intestinal epithelium and are thought to be largely homogeneous. Although quiescent intestinal stem cell (ISC) populations have been described, the identity and features of such a population remain controversial. Here we report unanticipated heterogeneity within the Lgr5+ ISC pool. We found that expression of the RNA-binding protein Mex3a labels a slowly cycling subpopulation of Lgr5+ ISCs that contribute to all intestinal lineages with distinct kinetics. Single-cell transcriptome profiling revealed that Lgr5+ cells adopt two discrete states, one of which is defined by a Mex3a expression program and relatively low levels of proliferation genes. During homeostasis, Mex3a+ cells continually shift into the rapidly dividing, self-renewing ISC pool. Chemotherapy and radiation preferentially target rapidly dividing Lgr5+ cells but spare the Mex3a-high/Lgr5+ population, helping to promote regeneration of the intestinal epithelium following toxic insults. Thus, Mex3a defines a reserve-like ISC population within the Lgr5+ compartment.


Assuntos
Proliferação de Células/fisiologia , Mucosa Intestinal/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/metabolismo , Animais , Mucosa Intestinal/citologia , Camundongos , Camundongos Transgênicos , Proteínas de Ligação a RNA/genética , Receptores Acoplados a Proteínas G/genética , Células-Tronco/citologia
10.
Stem Cell Reports ; 5(6): 979-987, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26549850

RESUMO

Insertion of reporter cassettes into the Lgr5 locus has enabled the characterization of mouse intestinal stem cells (ISCs). However, low cell surface abundance of LGR5 protein and lack of high-affinity anti-LGR5 antibodies represent a roadblock to efficiently isolate human colonic stem cells (hCoSCs). We set out to identify stem cell markers that would allow for purification of hCoSCs. In an unbiased approach, membrane-enriched protein fractions derived from in vitro human colonic organoids were analyzed by quantitative mass spectrometry. Protein tyrosine pseudokinase PTK7 specified a cell population within human colonic organoids characterized by highest self-renewal and re-seeding capacity. Antibodies recognizing the extracellular domain of PTK7 allowed us to isolate and expand hCoSCs directly from patient-derived mucosa samples. Human PTK7+ cells display features of canonical Lgr5+ ISCs and include a fraction of cells that undergo differentiation toward enteroendocrine lineage that resemble crypt label retaining cells (LRCs).


Assuntos
Moléculas de Adesão Celular/análise , Separação Celular/métodos , Colo/citologia , Receptores Proteína Tirosina Quinases/análise , Células-Tronco/citologia , Proliferação de Células , Células Cultivadas , Colo/ultraestrutura , Humanos , Espectrometria de Massas , Técnicas de Cultura de Órgãos , Células-Tronco/química
11.
Nat Genet ; 47(4): 320-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25706628

RESUMO

Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-ß signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-ß in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-ß signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Fibroblastos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Análise por Conglomerados , Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Camundongos , Camundongos Nus , Análise em Microsséries , Invasividade Neoplásica , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Prognóstico , Células Estromais/metabolismo , Células Estromais/patologia , Transcriptoma
12.
Nat Cell Biol ; 16(7): 695-707, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24952462

RESUMO

Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with ß-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion.


Assuntos
Adenoma , Receptores de Proteínas Morfogenéticas Ósseas/genética , Neoplasias Colorretais/fisiopatologia , Fator de Transcrição GATA6/metabolismo , Regulação Neoplásica da Expressão Gênica , Células-Tronco/citologia , Células-Tronco/metabolismo , Adenoma/patologia , Animais , Antineoplásicos/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Proliferação de Células , Feminino , Imunofluorescência , Fator de Transcrição GATA6/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Células-Tronco/efeitos dos fármacos , Proteínas Wnt/metabolismo
13.
Bio Protoc ; 4(9)2014 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-29104885

RESUMO

We sought to understand the mechanisms behind the potent effect of stromal TGF-beta program on the capacity of colorectal cancer (CRC) cells to initiate metastasis. We discovered that mice subcutaneous tumors and metastases generated in the context of a TGF-beta activated microenvironment displayed prominent accumulation of p-STAT3 in CRC cells compared with those derived from control cells. STAT3 signaling depended on GP130 as shown by strong reduction of epithelial p STAT3 levels upon GP130 shRNA-mediated knockdown in CRC cells.

14.
Arq Bras Cir Dig ; 26(3): 184-9, 2013.
Artigo em Inglês, Português | MEDLINE | ID: mdl-24190375

RESUMO

BACKGROUND: Ultrasound, computed tomography, and magnetic resonance imaging of abdominal wall has increasingly been used for hernia diagnosis when clinical examination is uncertain. Anatomical study of abdominal wall along with the ultrasound of transversus abdominis muscle aponeurosis can help identify a Spigelian hernia in this region, a disease of difficult diagnosis. AIM: To compare the ultrasound findings of anterolateral wall of the abdomen, focusing on Spigelian aponeurosis, to the anatomy of abdominal wall studied in cadavers. METHODS: The evaluation of the transversus abdominis aponeurosis was performed during routine ultrasound exams of the anterolateral wall of the abdomen in 90 individuals of both genders, over 25 years, and data were correlated with 60 dissections of the abdominal wall, held on cadavers. RESULTS: Ultrasound showed no significant defects in the aponeurosis of transversus abdominis muscle in the 90 subjects studied and the width of the Spigelian aponeurosis ranged from 0.83 to 2.93 cm (mean 1.72 cm). During dissections of the transversus abdominis, some defects were found in 14 out of 60 muscles and aponeurosis studied (23.3%) and the width of the Spigelian aponeurosis ranged from 1.5 to 3.5 cm (mean 2.26 cm). Comparisons between age groups and genders evaluated by ultrasound with cadaver dissections performed were not statistically significant. CONCLUSION: Sonographic examinations found no defects in the aponeurosis of transversus abdominis muscle compatible with hernias, and anatomical variations and defects found during dissections were not as well accompanied by Spigelian hernias in the studied corpse.


Assuntos
Músculos Abdominais/anatomia & histologia , Músculos Abdominais/diagnóstico por imagem , Adulto , Cadáver , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
15.
ABCD (São Paulo, Impr.) ; 26(3): 184-189, jul.-set. 2013. ilus, tab
Artigo em Português | LILACS | ID: lil-689675

RESUMO

RACIONAL: A avaliação da parede abdominal pela ultrassonografia, tomografia computadorizada e ressonância magnética tem sido cada vez mais indicada para auxiliar no diagnóstico das hérnias quando o exame clínico deixa dúvidas. A correlação de estudos da anatomia da parede abdominal com o exame ultrassonográfico da aponeurose do músculo transverso do abdome pode auxiliar no diagnóstico de uma hérnia desta localização, a hérnia de Spiegel, que se apresenta como doença de diagnóstico clínico difícil. OBJETIVO: Comparar os achados ultrassonográficos da parede anterolateral do abdome, com foco na aponeurose de Spiegel, e a anatomia da parede abdominal estudada em cadáveres não fixados. MÉTODO: A avaliação da aponeurose do músculo transverso do abdome foi realizada durante exames ultrassonográficos de rotina da parede anterolateral do abdome em 90 indivíduos de ambos os gêneros, maiores de 25 anos e estes dados foram relacionados com 60 dissecções da parede abdominal realizadas em cadáveres não fixados. RESULTADOS: Os exames ultrassonográficos não evidenciaram falhas significativas na aponeurose do músculo transverso do abdome nos 90 indivíduos estudados e a largura das aponeuroses de Spiegel variou de 0,83 a 2,93 cm (média de 1,72 cm). Durante as dissecções do transverso do abdome foram encontradas alterações anatômicas em 14 de 60 músculos e aponeuroses estudadas (23,3%) e a largura da aponeurose de Spiegel variou de 1,5 a 3,5 cm (média de 2,26 cm). A comparação entre os grupos etários e gêneros avaliados pelo estudo ultrassonográfico com as dissecções efetuadas em cadáveres não apresentou significância estatística. CONCLUSÃO: Os exames ultrassonográficos não encontraram defeitos na aponeurose do músculo transverso do abdome compatíveis com hérnias, assim como as variações anatômicas e os defeitos encontrados durante as dissecções também não foram acompanhados de hérnias de Spiegel nos cadáveres estudados.


BACKGROUND: Ultrasound, computed tomography, and magnetic resonance imaging of abdominal wall has increasingly been used for hernia diagnosis when clinical examination is uncertain. Anatomical study of abdominal wall along with the ultrasound of transversus abdominis muscle aponeurosis can help identify a Spigelian hernia in this region, a disease of difficult diagnosis. AIM: To compare the ultrasound findings of anterolateral wall of the abdomen, focusing on Spigelian aponeurosis, to the anatomy of abdominal wall studied in cadavers. METHODS: The evaluation of the transversus abdominis aponeurosis was performed during routine ultrasound exams of the anterolateral wall of the abdomen in 90 individuals of both genders, over 25 years, and data were correlated with 60 dissections of the abdominal wall, held on cadavers. RESULTS: Ultrasound showed no significant defects in the aponeurosis of transversus abdominis muscle in the 90 subjects studied and the width of the Spigelian aponeurosis ranged from 0.83 to 2.93 cm (mean 1.72 cm). During dissections of the transversus abdominis, some defects were found in 14 out of 60 muscles and aponeurosis studied (23.3%) and the width of the Spigelian aponeurosis ranged from 1.5 to 3.5 cm (mean 2.26 cm). Comparisons between age groups and genders evaluated by ultrasound with cadaver dissections performed were not statistically significant. CONCLUSION: Sonographic examinations found no defects in the aponeurosis of transversus abdominis muscle compatible with hernias, and anatomical variations and defects found during dissections were not as well accompanied by Spigelian hernias in the studied corpse.


Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Abdominais/anatomia & histologia , Músculos Abdominais , Cadáver
16.
Cancer Cell ; 22(5): 571-84, 2012 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-23153532

RESUMO

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-ß pathway, yet, paradoxically, they are characterized by elevated TGF-ß production. Here, we unveil a prometastatic program induced by TGF-ß in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-ß on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-ß-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-ß stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.


Assuntos
Neoplasias Colorretais/patologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Neoplasias Colorretais/tratamento farmacológico , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Receptor gp130 de Citocina/fisiologia , Células HT29 , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Interleucina-11/fisiologia , Camundongos , Metástase Neoplásica/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Recidiva , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais , Células Estromais/metabolismo , Células Estromais/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
17.
Nat Cell Biol ; 13(9): 1100-7, 2011 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-21804545

RESUMO

The formation and maintenance of complex organs requires segregation of distinct cell populations into defined territories (that is, cell sorting) and the establishment of boundaries between them. Here we have investigated the mechanism by which Eph/ephrin signalling controls the compartmentalization of cells in epithelial tissues. We show that EphB/ephrin-B signalling in epithelial cells regulates the formation of E-cadherin-based adhesions. EphB receptors interact with E-cadherin and with the metalloproteinase ADAM10 at sites of adhesion and their activation induces shedding of E-cadherin by ADAM10 at interfaces with ephrin-B1-expressing cells. This process results in asymmetric localization of E-cadherin and, as a consequence, in differences in cell affinity between EphB-positive and ephrin-B-positive cells. Furthermore, genetic inhibition of ADAM10 activity in the intestine of mice results in a lack of compartmentalization of Paneth cells within the crypt stem cell niche, a defect that phenocopies that of EphB3-null mice. These results provide important insights into the regulation of cell migration in the intestinal epithelium and may help in the understanding of the nature of the cell sorting process in other epithelial tissues where Eph-ephrin interactions play a central role.


Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Caderinas/metabolismo , Células Epiteliais/metabolismo , Proteínas de Membrana/metabolismo , Receptores da Família Eph/metabolismo , Transdução de Sinais , Proteínas ADAM/genética , Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide/genética , Animais , Western Blotting , Caderinas/genética , Adesão Celular , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Celulas de Paneth/metabolismo , Ligação Proteica , Interferência de RNA , Receptor EphB1/genética , Receptor EphB1/metabolismo , Receptor EphB3/genética , Receptor EphB3/metabolismo , Receptores da Família Eph/genética , Nicho de Células-Tronco
18.
Cell Stem Cell ; 8(5): 511-24, 2011 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-21419747

RESUMO

A frequent complication in colorectal cancer (CRC) is regeneration of the tumor after therapy. Here, we report that a gene signature specific for adult intestinal stem cells (ISCs) predicts disease relapse in CRC patients. ISCs are marked by high expression of the EphB2 receptor, which becomes gradually silenced as cells differentiate. Using EphB2 and the ISC marker Lgr5, we have FACS-purified and profiled mouse ISCs, crypt proliferative progenitors, and late transient amplifying cells to define a gene program specific for normal ISCs. Furthermore, we discovered that ISC-specific genes identify a stem-like cell population positioned at the bottom of tumor structures reminiscent of crypts. EphB2 sorted ISC-like tumor cells display robust tumor-initiating capacity in immunodeficient mice as well as long-term self-renewal potential. Taken together, our data suggest that the ISC program defines a cancer stem cell niche within colorectal tumors and plays a central role in CRC relapse.


Assuntos
Células-Tronco Adultas/metabolismo , Neoplasias do Colo/diagnóstico , Intestinos/patologia , Células-Tronco Neoplásicas/metabolismo , Receptor EphB3/metabolismo , Células-Tronco Adultas/patologia , Animais , Diferenciação Celular , Separação Celular , Extensões da Superfície Celular/patologia , Células Cultivadas , Neoplasias do Colo/patologia , Neoplasias do Colo/fisiopatologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Knockout , Recidiva Local de Neoplasia , Células-Tronco Neoplásicas/patologia , Prognóstico , Receptor EphB3/genética , Receptores Acoplados a Proteínas G/metabolismo , Nicho de Células-Tronco
19.
Rev. imagem ; 8(1): 15-6, jan.-mar. 1986.
Artigo em Português | LILACS | ID: lil-37997

RESUMO

Vários métodos säo utilizados para o diagnóstico de hemorragia gastro-intestinal, sendo os radioisotópicos principais: enxofre coloidal marcado com tecnécio - 99m, mais útil para hemorragias baixas e agudas e hemácias marcadas com tecnésio - 99m, para hemorragias intermitentes do abdome superior


Assuntos
Hemorragia Gastrointestinal , Coloide de Enxofre Marcado com Tecnécio Tc 99m
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